Amine derivative fixed to resin and method for synthesizing β-aminocarbonyl compound in a solid phase

ABSTRACT

The invention provides a resin-immobilized imine represented by the following formula: 
     
       
         P—Q—N—═CH—R   I  
       
     
     [in the formula, P represents the principal chain of a resin polymer; Q represents a substituted or unsubstituted hydrocarbon side chain or a substituted or unsubstituted hydrocarbon side chain with a heteroatom interposed therein; R represents a substituted or unsubstituted hydrocarbon group or heterocyclic group] and a resin-immobilized β-aminocarbonyl compound of the following formula:                    
     which can be released as β-aminocarbonyl compound from the solid phase; and the invention also provide a resin-immobilized amine of the following formula: 
     
       
         —P—Q 1 —O—Q 2 —NH 2    III  
       
     
     [Q 1  and Q 2  independently represent a hydrocarbon chain such as arylene, alkylenearylene or arylenealkylene], which is essential for solid state synthesis; and the invention has enabled the solid state synthesis of β-aminocarbonyl compound by the application of iminoaldol reaction.

This application is a 371 of PCT/JP99/0122, filed Mar. 12, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a resin-immobilized amine derivativeand a solid state synthesis method of β-aminocarbonyl compound.

2. Description of the Related Art

For peptide synthesis, for example, solid state synthesis methods usingresin carriers have been known conventionally. Such solid statesynthesis methods are effective means for simultaneous synthesis of agroup of numerous types of analogous compounds. It has been suggestedthat solid state synthesis methods are applicable to various chemicalreactions.

Practically, however, reactions to which solid state reaction isapplicable are limited, disadvantageously, compared with liquid phasereaction as the principal reaction for chemical synthesis.

In such circumstances of the related art concerning solid statesynthesis methods, the inventors of the present application haveinvestigated about the enhancement of the effectiveness of solid statesynthesis methods by efficiently progressing the most essential andimportant reaction for generating carbon—carbon bond in organicsynthesis in solid phase.

The inventors of the application have found a new method foriminoaldol-type addition reaction with a catalyst, using as the startingmaterial an imine compound recovered from the reaction of an aminecompound with aldehydes. Therefore, it has increasingly been animportant problem to establish a solid state synthesis method capable ofpractically more enhancing the efficiency of the method.

It is therefore a purpose of the invention of the application to providenew technical means for realizing the iminoaldol-type addition reactionas described above by a solid state synthesis method; more specifically,it is a purpose of the invention to provide a method for synthesizingβ-aminocarbonyl compounds, comprising applying a solid state synthesisreaction.

SUMMARY OF THE INVENTION

So as to attain the foregoing objectives, the present applicationprovides a resin-immobilized β-aminocarbonyl compound represented by thefollowing formula in a first aspect of the invention:

wherein P represents the principal chain of a resin polymer; Qrepresents a substituted or unsubstituted hydrocarbon side chain or asubstituted or unsubstituted hydrocarbon side chain with a heteroatominterposed therein; R, and R² and R³ independently represent asubstituted or unsubstituted hydrocarbon group or heterocyclic group; R¹represents —OR⁰, —SR⁰ or R⁰ (R⁰ represents a substituted orunsubstituted hydrocarbon group or heterocyclic group).

In a second aspect of the invention, the application provides aresin-immobilized β-aminocarbonyl compound of the aforementioned formulawhere, the hydrocarbon side chain Q represents the following formula:

—Q₁—O—Q₂— (in formula, Q₁ and Q₂ independently represent a substitutedor unsubstituted hydrocarbon chain such as arylene, alkylenearylene orarylenealkylene).

The application provides a method for producing a resin-immobilizedβ-aminocarbonyl compound in a third aspect of the invention, comprisingallowing a resin immobilized imine of the formula I: P—Q—N═CH—R to reactwith a silyl ether.

In a fourth aspect of the invention, the application provides a methodfor producting β-aminocarbonyl compound represented by either one of thefollowing formulas (A)

(where Q⁰ represents a substituent which is the remaining part of theside chain Q after the β-aminocarbonyl compound is separated from theresin) or (B)

comprising the cleavage of the β-aminocarbonyl from the resin of theresin-immobilized β-aminocarbonyl compound.

In a fifth aspect of the invention, the application provides a methodfor producing a β-aminocarbonyl compound, comprising treatment of theresin-immobilized β-aminocarbonyl compound of above formula II with aLewis acid.

DETAILED DESCRIPTION OF THE INVENTION

The application provides a resin-immobilized β-aminocarbonyl compoundrepresented by the formula II according to the first and second aspectsof the invention. These have never been know to enable the solid statesynthesis method of β-aminocarbonyl compounds.

In the resin-immobilized β-aminocarbonyl compound of the formula II, asdescribed above, P represents the principal chain of a resin polymer andQ represents a side chain to bind to the principal chain, wherein theresin polymer composing the principal chain includes any of additionpolymers, condensed polymers and cross-linked polymers thereof butpreferably includes addition polymers of alkenes with carbon—carbondouble bond or cross-linked polymers thereof. The alkenes includealiphatic olefins and aliphatic dienes and also include, α, β-aliphaticunsaturated carboxylic acids or esters thereof, α, β-aliphaticunsaturated nitriles and aromatic alkenes such as styrene,α-methylstyrene and divinylbenzene. The addition polymers thereof orpartially cross-linked polymers thereof are preferable.

It is needless to say that various condensed polymers of polyester,epoxy resins, polyether and polyamide are also included.

In accordance with the invention, the side chain Q includes substitutedor unsubstituted hydrocaron chains or substituted or unsubstitutedhydrocarbon chains with heteroatoms such as oxygen atom or nitrogen atominterposed therein, wherein the hydrocarbon chains then include varioushydrocarbon chains such as aliphatic, alicyclic, aromatic and aromaticaliphatic hydrocarbon chains and are for example alkylene chainrepresented by —(CH₂)_(n)— and phenylenealkylene chain. Otherwise, thehydrocarbon chains can satisfactorily be hydrocarbon chains withheteroatoms interposed therein.

These side chains Q are satisfactorily formed together with theprincipal chain P and are also satisfactorily formed by graftpolymerization after the principal chain P is formed.

As the side chain Q, for example, hydrocarbon chains derived from theresin-immobilized amine P—Q₁—O—Q₂—NH₂ are provided in accordance withthe invention, wherein Q₁ and Q₂ are arylene, alkylenearylene orarylenealkylene. Specifically, preferable examples of the hydrocarbonchains are hydrocarbon chains with Ph (pheylene chain), such as —Ph—,—(CH₂)_(n)—Ph, —PH—(CH₂)_(n)—, —Ph—(CH₂)_(n)—Ph—, particularlyoxyphenylene chains, such as —Ph—O—Ph—, —Ph—(CH₂)_(n)—O—Ph—,—Ph—(CH₂)_(n)—O—(CH₂)_(n)—Ph.

These hydrocarbons can satisfactorily have various substituents with noinhibition of the solid state synthesis reaction but with an activity toactivate the reaction. The substituents include hydrocarbon groups suchas alkyl group and aryl group, halogen atom, alkoxyl group, acyloxygroup, alkoxycarbonyl group, nitro group, cyano group and heterocyclicgroup.

R, R² and R³, and R⁰ composing R¹ in the resin-immobilizedβ-aminocarbonyl group of the formula II represent substituted orunsubstituted hydrocarbon groups or heterocyclic groups, wherein thehydrocabon groups include various linear or cyclic aliphatic or aromaticor aromatic aliphatic hydrocarbon groups, saturated or unsaturated.Similary, the heterocyclic groups include various heterocyclic groupscontaining oxygen or nitrogen. These are satisfactorily substituted withvarious substituents with no inhibition of the solid state synthesisreaction but with an activity to activate the reaction, for examplehydrocarbon groups such as alkyl group and aryl group, halogen atom,alkoxyl group, acyloxy group, alkoxycarbonyl group, nitro group, cyanogroup and heterocyclic group.

In accordance with the invention, further, the resin-immoiblized amineof the formula III P—Q₁—O—Q₂—NH₂ is provided as a substrate for thesolid state synthesis of compounds containing nitrogen such as aminogroup. The resin-immobilized amine is essentially required forconstructing a library of nitrogen-containing compounds for the solidstate synthesis.

For example, —Q₁—O—Q₂— is more specifically described as such astructure as —Ph—CH₂—O—Ph—CH₂—.

The reaction of various resin-immobilized amines including theresin-immobilized amine with aldehydes generates the resin-immobilizedamine (imine?) of the formula I.

The resin-immobilized amine of the formula P—Q—NH₂ or P—Q₁—O—Q₂-NH₂, asproduced by aminating for example a resin polymer of a structure P—QHand P—QX (in the formula, X represents halogen atom) or reducing anamide of the formula P—Q₁—O—Q₂—CONH₂ (in the formula, Q₁ represents apart of the side chain Q), is allowed to react with aldehydes.

The resin-immobilized imine synthesis through the reaction withaldehydes is appropriately carried out in a solvent at a temperature ofabout −10 to 70° C., preferably about 10 to 60° C. The solventappropriately includes DMF, DMSO, nitriles and halogenated hydrocarbons.

During the reaction, aldehydes are appropriately used at an equivalentweight ratio to the resin-immobilized imine within a range of 1 to 10during the reaction.

The resin-immobilized imine represented by the formula I can be used asa substrate for solid-phase iminoaldol reaction. The reaction is carriedout by allowing the resin-immobilized imine of the formula I to reactwith the silyl ethers.

The solid state reaction with the silyl ethers is progressed in asolvent, using for example a rare earth Lewis acid catalyst. As thesolvent, for example, use can be made of halogenated hydrocarbons,aromatic hydrocarbons, ethers, nitriles, alcohols and water orappropriate mixture solvents thereof.

The rare earth Lewis acid satisfactorily includes rare earth metalcompounds with Lewis acidity, for example organic acid ester salts,alcoholates, organic metal compounds and organic complex compounds ofrare earth elements such as ytterbium (Yb), scandium (Sc), yttrium (Y),lanthanoid (La), samarium (Sm) and neodium (Nd). Among them, rare earthtriflate for example Yb(OTf)₃ is more appropriate.

The silyl ethers are used at an equivalent weight ratio of generally 0.5to 10, preferably 1 to 7 to the resin-immobilized imine. The rare earthLewis acid actalyst is used at an equivalent weight ratio of generally0.01 to 1, preferably about 0.1 to 0.6.

The reaction temperature is appropriately −20 to 60° C., more preferablyambient temperature or therearound.

In accordance with the invention, the resin-immobilized β-aminocarbonylcompound can be recovered by the solid state reaction.

Together with the amine and imine, the resin-immobilized β-aminocarbonylcompound serves as important means for constructing a library of variousnitrogen-containing organic compounds.

By cleavage of the β-aminocarbonyl compound from the immobilizing resin,the β-aminocarbonyl compound of either one of the formulas A and B canbe recovered.

As shown in the following examples, for example, the selectivity to theformula A or B depends on the conditions for the cleavage reaction.

Lewis acid is effectively used for the cleavage reaction. By using Lewisacid, the β-aminocarbonyl compound can be detached under mild conditionsin a smooth manner. Oxidative cleavage is also effective.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention will now be described in more detail in the followingexamples.

EXAMPLE 1

According to the following reaction scheme, chloromethylated polystyrene1 reacted with p-hydroxybenzamide in the presence of sodium hydroxide,followed by reduction with borane, to recover resin-immobilized amine

Benzaldehyde reacted with the resulting resin-immobilized amine 2, torecover the corresponding resin-immobilized imine 3.

According to the following reaction scheme, the resin-immobilized amine3 reacted with silyl ether in the presence of a rare earth Lewis acidcatalyst Yb (OTf)₃ of 20 mol % in a solvent dichloromethane at ambienttemperature:

[in the formula, TMS represents trimethylsilyl group]. The resultingresin-immobilized β-aminocarbonyl compound 4 was subjected to a releaseprocess from the solid phase by using Lewis acid, to recover β-aminoester as β-aminocarbonyl compound 5, wherein the hydroxybenzyl group isbonded to the amino group.

The silyl ether type and release conditions were modified. The resultsare shown below in Table 1.

TABLE 1

Conditions Yield (%)

11 TFA, 60° C., 3 h 73 11 TFMSA, rt, 3 h 63 11 TMSOTf (10 eq), CH₂Cl₂,rt, 3 h 82

12 TMSOTf (10 eq), CH₂Cl₂, rt, 3 h 78

The physico-chemical properties are shown below.

R═Ph, R², R³═Me, R¹═OMe

TABLE 2 ¹H 1. 03 (3 H, s), 1. 11 (3 H, s), 3. 32 (1 H, d, 13. 2 Hz), 3.57 (1 H, d, 13. 2 Hz), 3. 65 (3 H, s), 3. 88 (1 H, s), 6. 74 (2 H, d, 8.6 Hz), 7. 06 (2 H, d, 8. 6 Hz), 7. 25- 7. 36 (5 H, m) ¹³C 19. 5. 24. 2,47. 6, 50. 9, 52 0. 67, 7, 115. 1, 127. 5, 128. 0, 129. 1. 129. 7, 132.4, 139. 1, 154. 8, 178. 2 IR 3397, 1734 cm⁻¹

EXAMPLE 2

The same procedures as in Example 1 were carried out, except for the useof the rare earth Lewis acid catalyst at 30 mol % for reaction ofvarious resin-immobilized imines with silyl ether and except that theresulting product was released from the solid phase by using a Lewisacid TMSOTf.

The results are shown in Table 3.

TABLE 3

R

Yield (%) Ph

52 p-Cl-Ph

11 58

11 95

11 53 C₈H₁₁ 11 60 2-Phenylethy 11 56

The physico-chemical properties are shown below.

R═Ph, R², R⁰═H, R¹═SE t

TABLE 4 ¹H 1. 21 (3 H, t, 7. 5 Hz), 2. 81-2. 99 (4 H, m), 3. 45 (1 H, d,11. 7 Hz), 3. 55 (1 H, d, 11. 7 Hz), 4. 15 (1H, dd, 5. 0, 8. 6 Hz), 6 73(2 H, d, 8. 4 Hz), 7. 10 (2 H, d, 8. 4 Hz), 7. 19- 7. 40 (5 H, m), ¹³C12. 3. 21. 4, 47, 8, 51. 3, 58. 9, 115. 6, 127. 3, 128. 2. 128. 7, 130.2. 131. 4, 141. 2, 198. 2 R = Ph—Cl, R³ = Me, R¹ = OMe

TABLE 5 ¹H 1. 02 (3 H, s), 1. 09 (3 H, s), 3. 29 (1 H, d, 13. 2 Hz), 3.55 (1 H, d, 13. 2 Hz), 3. 64 (3 H, s), 3. 84 (1 H, s), 6. 75 (2 H, d, 8.6 Hz) 7. 05 (2 H, d, 8. 6 Hz), 7. 20 (2 H, d, 8. 4 Hz), 7. 31 (2 H, d,8. 4 Hz) ¹³C 19. 5, 24. 0, 31. 0, 47. 3, 50. 7. 51. 9. 66. 9, 115. 0,128. 1, 129. 5, 130. 4, 132. 2, 133. 1, 137. 6, 154. 6, 177. 6 R =2-pyridyl, R² , R³ = Me, R¹ = Ome

TABLE 6 ¹H 1. 06 (3 H, s) 1. 14 (3 H, s), 3. 30 (1 H, d, J = 13. 2 Hz),3. 57 (1 H, d, J = 13. 2 Hz), 3. 64 (3 H, s), 3. 96 (1 H, s), 6. 70 (2H, d, J = 8. 6 Hz), 7. 05 (2 H, d, J = 8. 6 Hz), 7. 20 (2 H, m), 7. 64(1 H, t, 7. 7 Hz), 8. 60 (1 H, d, J = 4. 2 Hz) ¹⁰C 19. 9, 23. 5, 47. 6,51. 4, 51. 8, 67. 7, 115. 0, 122. 3. 124. 6, 129. 6, 135. 7, 149, 0,154. 8, 177. 6 R = cyclohexyl, R², R³ = Me, R¹ = OMe

TABLE 7 ¹H 1. 14 (3 H, s), 1. 18 (3 H, s), 1. 25-1. 65 (10 H, m), 2. 09(1 H, m), 2. 66 (1 H, m), 3. 64 (3 H, s), 3. 73 (1 H, d, 12. 6 Hz), 3.88 (1 H, d, 12. 6 Hz), 6. 76 (2 H, d, 8. 4 Hz), 7. 18 (2 H, d, 8. 4 Hz)R = phenyletheyl, R², R³ = Me, R¹ = OMe

TABLE 8 ¹H 1. 08 (3 H, s), 1. 15 (3 H, s), 1. 55 (2 H, m, 2. 48-2. 60 (2H, m), 3. 63 (3 H, s) 3. 71 (1 H, 12. 3 Hz), 3. 84 (1 H, d, 12. 3 Hz),6. 70-6. 74 (3 H, m), 7. 10-7. 28 (6 H, m) ¹³C 21. 4, 21. 8, 29. 7. 32.8, 47. 7, 51. 8, 54. 0, 63. 3, 115. 3, 126. 0, 126. 5, 128. 3, 128. 4,129. 4, 132. 1. 165. 9, 175. 1 IR 3337, 1732

EXAMPLE 3

The same procedures as in Example 2 were carried out except for the useof DDQ for releasing the product from the solid phase. The results areshown in Table 9.

TABLE 9

R

Yield (%) Ph 11 64 Ph 12 53 C₈H₁₁ 11 61

The physico-chemical properties are shown below.

R═Ph, R², R³═Me, R¹═OMe

TABLE 10 ¹H 1. 09 (3 H, s), 1. 15 (3 H, s), 3. 70 (3 H, s), 4. 24 (1 H,s), 7. 28-7, 35 (5 H, m) ¹³C 20. 6, 24. 2, 52. 0, 55. 7, 64. 5, 127, 4,127. 8, 127. 9, 128. 3, 176. 9 R = cyclohexyl, R², R³ = Me, R¹ = OMe

TABLE 11 ¹H 0. 99 (3 H, s), 1. 22 (3 H, s), 1. 46-1. 76 (10 H, m), 1. 96(1 H, m), 2. 84 (1 H, d, 6. 2 Hz), 3. 64 (3 H, s) ¹³C 19. 5, 22. 9, 25.4, 25. 7, 26. 9. 26. 2, 48. 4, 54. 5, 62. 0

INDUSTRIAL APPLICABILITY

As has been described above in detail, the solid state synthesis ofβ-aminocarbonyl compound through the application of iminoaldol reactionis attained in accordance with the invention of the application; andadditionally, a library of β-aminocarbonyl compounds can efficiently beconstructed.

What is claimed is:
 1. A resin-immobilized β-aminocarbonyl compoundrepresented by the following formula:

wherein, P represents the principal chain of a resin polymer; Qrepresents a substituted or unsubstituted hydrocarbon side chain or asubstituted or unsubstituted hydrocarbon side chain with a heteroatominterposed therein; R and R² and R³ independently represent asubstituted or unsubstituted hydrocarbon group or heterocyclic group; R¹represents —OR⁰, SR⁰ or R⁰ where R⁰ represents a substituted orunsubstituted hydrocarbon group or heterocyclic group.
 2. Theresin-immobilized β-aminocarbonyl compound according to claim 1 whereinthe hydrocarbon side chain Q represents the following formula: Q₁—O—Q₂—where, Q₁ and Q₂ independently represent a substituted or unsubstitutedhydrocarbon chain.
 3. The resin-immobilized β-aminocarbonyl compoundaccording to claim 2 wherein Q₁ and Q₂ independently represent arylene,alkylenearylene or arylenealkylene.
 4. A method for producing a resinimmobilized β-aminocarbonyl compound according to claim 1 or 2comprising allowing a resin-immobilized imine of the formula I:P—Q—N═CH—R to react with a silyl ether.
 5. A method for producing aβ-aminocarbonyl compound represented by at least one of the followingformulas (A)

where Q⁰ represents a substituent which is the remaining part of theside chain Q after the β-aminocarbonyl compound is separated from theresin

which comprises cleavage of the β-aminocarbonyl from the resin of theresin-immobilized β-aminocabonyl compound of claim 1 or
 2. 6. A methodfor producing a β-aminocarbonyl compound which comprises treatment ofthe β-aminocarbonyl compound of claim 1 or 2 with a Lewis acid.